Clinical question
Should supplementation with arginine and micronutrients versus no supplementation be used to promote healing in adults with PIs?
Context
Population:
Intervention:
Comparison:
Main Outcomes:
Setting:
Conflicts on Interest:
Adults who have a pressure injury
Arginine and micronutrient supplement
Standard diet or standard supplement or placebo
Any clinical setting
Hierarchy of outcome measures:
Outcome 1: Time to healing
Outcome 2: Complete healing (total/percent healed)
Outcome 3: Change in wound size (% change)
Outcome 4: Pain
Outcome 5: If infected at baseline, changes in signs and symptoms of infection
No Guideline Governance Group members of Core Review Group members had a conflict of interest
Evidence to Decision Framework
(Click on the individual judgements for more information)
Summary of Judgements
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
Yes
Moderate
Large
Low
No important uncertainty or variability
Probably favors the intervention
Moderate costs
No included studies
Probably favors the intervention
Probably increased
Varies
Varies
1. Problem:
Is the problem (pressure injuries) a priority?
JUDGEMENT
No
Probably No
Probably Yes
Yes
Varies
Don’t Know
RESEARCH EVIDENCE
Treating pressure injuries to achieve healing is a priority to most individuals who experience a PI. In 2021, the Guideline Governance Group undertook a stakeholder survey on priority issues to address in the guideline. Receiving clinical guidance on nutritional interventions for treating pressure injuries (PIs) was rated as the highest priority by clinicians (median ranking 5/5) and people with or at risk of PIs and their informal carers (median ranking 5/5). Clinical guidance on nutritional interventions for treating PIs was rated as a high priority by researchers (median ranking 4/5) and industry representatives (median ranking 4/5).
In an earlier survey conducted by the previous Guideline Governance Group in 2018,(Haesler, Pittman et al. 2022) 71.8% (275/383) of individuals with or at risk of PIs and 65.3% (555/850) of informal carers rated receiving information on diet and hydration as important or very important.
2. Desirable Effects:
How substantial are the desirable anticipated effects?
JUDGEMENT
Trivial
Small
Moderate
Large
Varies
Don’t Know
RESEARCH EVIDENCE
| Outcome | Arginine and micronutrient supplement |
No supplement |
Difference | Relative effect |
|---|---|---|---|---|
| Median days to complete healing | 42 days | 85 days | 43 days | -- |
| Number completely healed | 17/101 (16.8%) | 10/99 (10.1%) | 68 more per 1000 (from 20 fewer to 248 more) |
RR 1.67 (0.80-3.46) |
| Change in PI surface area (%) | -- | Mean ranged from 3.32% increase to 45.2% decrease | Mean difference 15.8% 25.1% lower to 6.48% lower | -- |
Outcome 1: Median days to complete healing
One randomized controlled trial (RCT)(Banks, Webster et al. 2023) reported a Kaplan-Meier model for median days to PI healing for wound healing nutritional formulas enriched with L-arginine, vitamin C and zinc versus a standard hospital diet.** The study reported a non-significant reduction in time to healing for individuals receiving the arginine/micronutrient supplementation (median 42 days [95% CI: 33.8 to 50.2] versus median 85 days [95% CI 34.5 to 135.5] days control group [p=0.15]). There was no serious risk of bias (Torsy, Tency et al. 2025). Imprecision and inconsistency were not evaluable. Overall, time to complete healing is influenced by the size and severity of a PI at entry into the study (Langer, Wan et al. 2024), which appeared to be similar at baseline in the RCT (Banks, Webster et al. 2023).
Outcome 2: Complete PI healing
The forest plot (Langer, Wan et al. 2024) included only one RCT (Cereda, Klersy et al. 2015) reporting complete PI healing that compared a high protein nutritional supplement enriched with arginine, vitamin C, vitamin E, selenium and zinc to a supplement with no arginine/micronutrients for people with PIs. The supplements were taken for eight weeks. Participants were older adults in long term care, 70% of whom had unintentional weight loss and 70% of whom had a low body mass index (BMI). The PIs in the study were 40% Category/Stage 4, 30% Category/Stage 3 and 30% Category/Stage 2.
The analysis showed that arginine/micronutrient supplementation might be associated with more PIs achieving complete healing (relative risk [RR] 1.67, 95% CI 0.80 to 3.46), which translates to 68 more per 1,000 PIs (from 20 fewer to 248 more) achieving complete healing. However, there is low certainty in this result. The certainty was downgraded twice for imprecision because the CI overlaps the null effect and crosses the clinical decision threshold between recommending and not recommending treatment, as well as having also a low number of events and participants (Langer, Wan et al. 2024).
Outcome 3: Change in PI surface area (%)
The meta-analysis (Langer, Wan et al. 2024) included two RCTs (Cereda, Klersy et al. 2015, Banks, Ross et al. 2016) reporting percentage change in PI area that compared a nutritional supplement enriched with arginine and micronutrients to supplementation that did not include arginine/micronutrients. In both studies, the participants were diagnosed with or likely to have malnutrition. The analysis showed that a mean difference in PI area of 15.8 % lower (25.11 lower to 6.48 lower) with arginine/micronutrient supplementation. However, there is low certainty in this result. The certainty was downgraded once for risk of bias because one of the included studies was at an overall high risk of bias. The certainty was also downgraded once for imprecision because the 95% CI was narrow and the participant numbers were low (Langer, Wan et al. 2024),
** Regimens are described in the data extraction tables. Product names may have changed.
3. Undesirable Effects:
How substantial are the undesirable anticipated effects?
JUDGEMENT
Trivial
Small
Moderate
Large
Varies
Don’t Know
| Outcome | Arginine, and micronutrient supplement |
No supplement placebo |
Difference | Relative effect |
|---|---|---|---|---|
| Adverse GI tract events | 13/185 (7.0%) | 3/183 (1.6%) | 36 more per 1000 (from 2 more to 132 more) |
RR 3.20 (1.13 to 9.04) |
Outcome: Adverse GI events
Adverse gastrointestinal events
The meta-analysis (Langer, Wan et al. 2024) included four RCTs (Cereda, Klersy et al. 2015, Banks, Ross et al. 2016, Yamanaka, Okada et al. 2017, Banks, Webster et al. 2023) reporting adverse gastrointestinal tract (GIT) effects associated with a nutritional supplement enriched with arginine and micronutrients. Compared to not taking a supplement with arginine/micronutrients, there was a higher rate of GIT events associated with taking arginine/micronutrient supplements (7.0% vs 1.6%, RR 3.20, 95% CI1.13 to 9.04, p=0.03). This translated to 36 more individual per 1,000 experiencing an adverse GIT event (from 2 more to 132 more). However, there is low certainty in this result. The certainty was downgraded once for risk of bias because one of the included studies was at an overall high risk of bias (Langer, Wan et al. 2024, Torsy, Tency et al. 2025). The certainty was also downgraded twice for imprecision because the confidence interval (CI) overlaps the null effect and includes potential benefit (RR<0.75) and potential harm (RR>1.25) and because there was a low number of events and participants (Langer, Wan et al. 2024).
4. Overall certainty of evidence: What is the overall certainty of the evidence of effects?
JUDGEMENT
Very low
Low
Moderate
High
No included studies
RESEARCH EVIDENCE
| Outcome | Relative Importance | Certainty of Evidence |
|---|---|---|
| Median days to complete healing | CRITICAL | VERY LOW |
| Complete healing | CRITICAL | LOW |
| Change in PI surface area (%) | CRITICAL | LOW |
There is no core outcome set specific to pressure injury healing. To determine the relative importance of outcome measures, the GGG reviewed literature (Gottrup, Apelqvist et al. 2010, Augustin, Schmitt et al. 2014, Driver, Gould et al. 2017, Driver, Gould et al. 2019, Miranda, Deonizio et al. 2021, Raepsaet, Alves et al. 2023, Gupta, Goldstone et al. 2024, Zhang, Zhang et al. 2024), on PI and wound healing outcome measures and, in 2021, undertook a survey of stakeholders regarding their perspective on the importance of commonly reported wound healing outcomes. Based on the review and survey, the GGG prioritized consideration of the following five outcome measures of interest when evaluating evidence for interventions to support PI healing. These clinical outcomes were supported by all surveyed stakeholder groups as critically important to making decisions about the evidence, and are wound agnostic (Gupta, Goldstone et al. 2024), frequently reported in PI research (Miranda, Deonizio et al. 2021), and relevant to both clinical practice and quality of life for individuals with a PI (Driver, Gould et al. 2017, Driver, Gould et al. 2019).
Priority for outcome measures was:
Time taken to heal
Complete healing
Percent change in wound size
Wound-related pain
Changes in signs and symptoms of infection (if infected at baseline)
Certainty of evidence for outcome measures
Certainty of evidence for median days to healing was very low. Imprecision and inconsistency could not be evaluated.
Certainty of evidence for complete healing of PI was low. The certainty was downgraded twice for imprecision because the confidence interval (CI) overlaps the null effect and includes potential benefit (RR<0.75) and potential harm (RR>1.25). Additionally, there was a low number of events and participants (Langer, Wan et al. 2024).
Certainty of evidence for mean change in PI area (%) was low. The certainty was downgraded once for risk of bias due to an overall high risk of bias in one of the included studies (Langer, Wan et al. 2024). The certainty was also downgraded once for imprecision because although the 95% CI was narrow, the participant numbers were low (Langer, Wan et al. 2024).
5. Values:
Is there important uncertainty about or variability in how much people value the main outcomes?
JUDGEMENT
Important uncertainty or variability
Possibly important uncertainty or variability
Probably no important uncertainty or variability
No important uncertainty or variability
RESEARCH EVIDENCE
In a Delphi survey (Lechner, Coleman et al. 2022) that developed a core outcomes et for PI prevention trials, the outcome of PI occurrence was rated as being of critical important (score of 7-9) by all types of stakeholders (health professionals, people with or at risk of a PI and their informal carers, industry representatives and researchers). Greater than 90% of the 158 participants rated this outcome measure as critically important (Lechner, Coleman et al. 2022).
6. Balance of Effects:
Does the balance between desirable and undesirable effects favour the intervention or the comparison?
JUDGEMENT
Favors the comparison
Probably favors the comparison
Does not favor either the intervention or the comparison
Probably favors the intervention
Favors the intervention
Varies
Don’t know
RESEARCH EVIDENCE
The desirable effects were moderate desirable and undesirable were large. However, the undesirable effects were generally minor in nature and resolved on cessation of supplementation. The Guideline Governance Group determined that the balance of effects probably favors the intervention.
7. Resources Required:
How large are resource requirements (costs) of the intervention?
JUDGEMENT
Large costs
Moderate costs
Negligible costs and savings
Moderate savings
Large savings
Varies
Don’t know
RESEARCH EVIDENCE
In the Panel Group’s expert opinion, nutritional supplementation can be expensive, particularly for homeless people, people living in the community, people in long term institutional settings, and those without access to health insurance. This is a particular concern for people who require supplementation for longer duration. In acute care settings, particularly intensive care, nutritional supplements are usually funded within the costs of health care.
In the Guideline Governance Group’s expert opinion, the above costs represent moderate costs of implementing the nutritional supplementation
8. Certainty of evidence of required resources:
What is the certainty of evidence of resource requirements (costs) of the intervention?
JUDGEMENT
Very low
Low
Moderate
High
No included studies
RESEARCH EVIDENCE
The Guideline Governance Group considered the evidence above to have very low certainty. The evaluation by Shafrin and Wang (Shafrin, Wang et al. 2023) was based on a basic decision-tree model, with the assumptions on the effectiveness based on a non-randomized trial with 18 participants (Brewer, Desneves et al. 2010) and resource use extrapolated from a 2012 study (Dealey, Posnett et al. 2012). Thus, input data were not systematically searched for and may have been dated. The analysis was conducted by employees of a company providing the nutritional supplements.
9. Cost Effectiveness: Does the cost-effectiveness of the intervention favour the intervention or the comparison?
JUDGEMENT
Favors the comparison
Probably favors the comparison
Does not favor either the intervention or the comparison
Probably favors the intervention
Varies
No included studies
RESEARCH EVIDENCE
Cost modelling for supplementation of arginine/micronutrients was reported for one study (Cereda, Klersy et al. 2015, Cereda, Klersy et al. 2016). The analysis considered the difference in direct medical costs between groups that did and did not receive arginine/micronutrient supplements. The arginine/micronutrient supplements were more expensive (mean 173.40 versus 212.80, mean difference: 39.40 EUR, p < 0.001 [2015 in Italy). There was moderate certainty in this result, downgraded one level for imprecision because although the 95% CI did not overlap the null effect there was a low number of participants (Langer, Wan et al. 2024).
The study reported the incremental cost-effectiveness ratio (ICER) of arginine/micronutrient supplements related to the outcome measures with significant results—percentage change in PI area and 40% reduction in PI area at 8 weeks. There was an overall total cost saving (mean difference, –74.30 EUR; p = 0.013) (Cereda, Klersy et al. 2016).
A cost savings model suggested that introduction of a wound-specific oral nutritional supplement for nursing home patients with a PI would achieve economic benefit based on the accelerated wound healing time. Factors considered included nursing home costs, cost of nutritional supplement, PI treatment costs and nursing time for assessment, repositioning, and topical wound care. At a per patient/per episode level, cost savings was $6,319 for Category/ Stage 2 PI, $7,651 for Category/ Stage 3 PI and $16,579 for Category/ Stage 4 PI (USD, adjusted for inflation in analysis) (Shafrin, Wang et al. 2023). The Guideline Governance Group considered the evidence above to have very low certainty. The evaluation by Shafrin and Wang (Shafrin, Wang et al. 2023) was based on a basic decision-tree model, with the assumptions on the effectiveness based on a non-randomized trial with 18 participants (Brewer, Desneves et al. 2010) and resource use extrapolated from a 2012 study (Dealey, Posnett et al. 2012). Thus, input data were not systematically searched for and may have been dated. The analysis was conducted by employees of a company providing the nutritional supplements.
10. Inequity:
What would be the impact of recommending the intervention on health inequity?
JUDGEMENT
Reduced
Probably reduced
Probably no impact
Probably increased
Increased
Varies
Don’t know
RESEARCH EVIDENCE
In the Panel Group’s expert opinion, people who are at higher risk of nutritional deficits are also more likely to be unable to access nutritional supplementation due to their social circumstances and the cost of interventions. This includes barriers to accessing a dietitian to evaluate the person’s nutritional needs. In the Guideline Governance Group’s expert opinion, recommending nutritional supplementation would likely increase health inequity. There are barriers to accessing supplementation for many people depending on their geographic location and the clinical context.
11. Acceptability:
Is the intervention acceptable to key stakeholders?
JUDGEMENT
No
Probably no
Probably yes
yes
Varies
Don’t know
RESEARCH EVIDENCE
There is some evidence that arginine/micronutrient supplements are acceptable. In one study (Banks, Ross et al. 2016), there was a nonsignificant higher rate of non-adherence to supplementation compared with standard diet (29.67% versus 0%, RR 15.60, 95% CI 0.94 to 259, p=0.06, very low certainty of evidence) (Langer, Wan et al. 2024).
In the Panel Group’s expert opinion, a wide range of factors influence acceptability of nutritional supplements. These include palatability of thickened supplements and altered foods (e.g. pureed or thickened) and the person’s ability to consume the volume of fluid required for some supplements
In the Guideline Governance Group’s expert opinion, recommending nutritional supplementation would having varying acceptability from stakeholders.
12. Feasibility:
Is the intervention (limiting sitting time) feasible to implement?
JUDGEMENT
No
Probably no
Probably yes
yes
Varies
Don’t know
RESEARCH EVIDENCE
In the Panel Group’s expert opinion, barriers to implementation include access to a dietitian to ensure the intervention can be individualized to the person’s needs. Nutritional supplementation is not available in many clinical and geographic contexts, and in some contexts there are rigid referral mechanisms to access dietitians and nutritional interventions.
In the Panel Group’s expert opinion, people living in the community may be unable to implement the recommendation due to lack of relevant knowledge to select an appropriate supplement.
In the Guideline Governance Group’s expert opinion, the feasibility of implementing a recommendation to provide nutritional supplementation varies. In some contexts (e.g. most acute care settings) access to nutritional supplementation and the processes that support implementation (e.g. screening for nutritional deficits, dietician review, access to products) is highly feasible. In other contexts (e.g., community settings, low resource communities) implementing a recommendation to provide nutritional supplementation would not be feasible.
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